Ciliopathy Panel

Test code: KI0701

Is a 107 panel that includes assessment of non-coding variants.

Is ideal for patients with a clinical suspicion of Bardet-Biedl syndrome, , Meckel syndrome, with or without retinal dystrophy, or complex phenotype.

Isn’t ideal for a patient with primary ciliary dyskinesia or isomerism/heterotaxy. For patients with a suspicion of primary ciliary dyskinesia, Primary Ciliary Dyskinesia Panel is recommended. For patients with isomerism/heterotaxy, Heterotaxy and Panel is recommended.

About Ciliopathy

Ciliopathies are a group of disorders resulting from either abnormal formation or function of cilia. in ciliary gene are known to cause single organ phenotypes, as well as complex syndromes. have a broad range of phenotypes encompassing a number of different autosomal recessive, dominant and X-linked syndromes. As cilia are a component of almost all cells, ciliary dysfunction can manifest as a collection of features that include retinal degeneration, renal disease and brain malformations. Additional features may include congenital fibrocystic diseases of the and pancreas, , and skeletal dysplasias. Ciliopathies can result from a at a single locus in one patient while mutations affecting a number of different loci can, at the same time, can result in a similar phenotype in other patients. Ciliopathies can be classified according to whether there is aberrant function in an intact or complete absence/loss of the mature cilium. The latter is the case with severe multi-organ phenotypes.

Availability

4 weeks

Gene Set Description

Genes in the Ciliopathy Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD

ACVR2B Heterotaxy, visceral, 4, autosomal AD 1 2

AHI1 Joubert syndrome AR 62 93

ALMS1* Alström syndrome AR 197 302

ANKS6 Nephronophthisis AR 9 12

ARL13B Joubert syndrome AR 11 10

ARL6 Bardet-Biedl syndrome, AR 14 21

ARMC9 Joubert syndrome 30 AR 12 11

B9D1 Meckel syndrome AR 7 10

B9D2 Meckel syndrome AR 8 4

BBIP1# Bardet-Biedl syndrome 18 AR 1 1

BBS1 Bardet-Biedl syndrome AR 66 103

https://blueprintgenetics.com/ BBS10 Bardet-Biedl syndrome AR 90 107

BBS12 Bardet-Biedl syndrome AR 36 58

BBS2 Bardet-Biedl syndrome, Retinitis pigmentosa AR 58 91

BBS4 Bardet-Biedl syndrome AR 25 53

BBS5 Bardet-Biedl syndrome AR 18 31

BBS7 Bardet-Biedl syndrome AR 19 43

BBS9 Bardet-Biedl syndrome AR 27 52

C21ORF2 Retinal dystrophy with or without macular staphyloma (RDMS), AR 13 22 Spondylometaphyseal dysplasia, axial (SMDAX)

C2CD3 Orofaciodigital syndrome XIV AR 9 10

C5ORF42 Orofaciodigital syndrome, Joubert syndrome AR 97 103

C8ORF37 Retinitis pigmentosa, Cone rod dystrophy, Bardet-Biedl syndrome 21 AR 8 17

CC2D2A COACH syndrome, Joubert syndrome, Meckel syndrome AR 76 91

CENPF Ciliary dyskinesia -Lethal Ciliopathy AR 13 8

CEP104 Joubert syndrome AR 7 5

CEP120 Short-rib thoracic dysplasia 13 with or without AR 9 9

CEP164 Nephronophthisis AR 11 9

CEP19 Morbid obesity and spermatogenic failure, Bardet-Biedl syndrome AR 2 2

CEP290* Bardet-Biedl syndrome, Leber congenital amaurosis, Joubert syndrome, AR 130 289 Senior-Loken syndrome, Meckel syndrome

CEP41 Joubert syndrome AR/Digenic 7 11

CEP83 Nephronophthisis AR 10 10

CPE Obesity, severe, and type II diabetes AR 2

CRB2 Focal segmental glomerulosclerosis, Ventriculomegaly with cystic AR 12 22 disease

CSPP1 Jeune asphyxiating thoracic dystrophy, Joubert syndrome AR 32 27

DCDC2 Deafness, Nephronophthisis, Sclerosing cholangitis, neonatal AR 13 9

DDX59 Orofaciodigital syndrome V AR 2 6

DHCR7 Smith-Lemli-Opitz syndrome AR 88 217

DYNC2H1 Short -rib thoracic dysplasia with or without polydactyly type 1, Short -rib AR/Digenic 148 205 thoracic dysplasia with or without polydactyly type 3, Asphyxiating thoracic dysplasia (ATD; Jeune), SRPS type 2 (Majewski)

DYNC2LI1 Short-rib throacic dysplasia 15 with polydactyly AR 19 14

https://blueprintgenetics.com/ EVC Weyers acrofacial dysostosis, Ellis-van Creveld syndrome AD/AR 58 83

EVC2 Ellis-van Creveld syndrome, Weyers acrodental dysostosis AD/AR 78 75

FAM58A Toe syndactyly, telecanthus, and anogenital and renal malformations XL 8 11 (STAR syndrome)

GLI2 Culler-Jones syndrome AD 29 82

GLI3 , Pallister-Hall syndrome, Grieg AD 70 235 cephalopolysndactyly syndrome, Postaxial polydactyly type A, Preaxial polydactyly type 3, Preaxial polydactyly type 4

GLIS2 Nephronophthisis AR 3 3

HYLS1 AR 3 2

IFT122* Sensenbrenner syndrome, Cranioectodermal dysplasia (Levin- AR 13 23 Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2

IFT140 Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating AR 38 63 thoracic dysplasia (ATD; Jeune)

IFT172 Retinitis pigmentosa, Short -rib thoracic dysplasia with or without AR 22 25 polydactyly, Asphyxiating thoracic dysplasia (ATD; Jeune)

IFT27 Bardet Biedl syndrome 19 AR 1 4

IFT43 Cranioectodermal dysplasia 3 AR 4 7

IFT52 Short-rib thoracic dysplasia 16 with or without polydactyly AR 3 4

IFT80 Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating AR 11 11 thoracic dysplasia (ATD; Jeune)

IFT81 Short rib thoracic dysplasia with polydactyly, Cone-Rod dystrophy, AR 4 9 autosomal recessive

INPP5E Joubert syndrome, Mental retardation, truncal obesity, retinal dystrophy, AR 25 50 and micropenis (MORM syndrome)

INVS Nephronophthisis AR 16 34

IQCB1 Senior-Loken syndrome AR 24 41

KIAA0556 Joubert syndrome 26 AR 2 2

KIAA0586 Short rib thoracic dysplasia with polydactyly, Joubert syndrome AR 29 31

KIAA0753 Orofaciodigital syndrome XV AR 6 7

KIF14 Meckel syndrome 12 AR 9 16

KIF7 Acrocallosal syndrome, Hydrolethalus syndrome, Al-Gazali-Bakalinova AR/Digenic 24 44 syndrome, Joubert syndrome

LEFTY2* Left-right axis malformations AD 1 3

LZTFL1 Bardet-Biedl syndrome 17 AR 6 3

https://blueprintgenetics.com/ MAPKBP1 Nephronophthisis 20 AR 6 7

MKKS Bardet-Biedl syndrome, McKusick-Kaufman syndrome AR 21 59

MKS1 Bardet-Biedl syndrome, Meckel syndrome AR 50 52

NEK1 Short -rib thoracic dysplasia with or without polydactyly, SRPS type 2 AR/Digenic 22 23 (Majewski)

NEK8 Nephronophthisis AR 16 18

NODAL Heterotaxy, visceral AD 4 15

NPHP1 Nephronophthisis, Joubert syndrome, Senior-Loken syndrome AR 19 76

NPHP3 Nephronophthisis, Renal-hepatic-pancreatic dysplasia, Meckel syndrome AR 38 75

NPHP4 Nephronophthisis, Senior-Loken syndrome AR 20 113

OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital XL 153 160 syndrome, Joubert syndrome

PDE6D Joubert syndrome 22 AR 3 1

PKD1* Polycystic AD 237 1923

PKD2 Polycystic kidney disease AD 55 333

PKHD1 Polycystic kidney disease AR 249 557

PMM2 Congenital disorder of glycosylation AR 76 128

PNPLA6 Laurence-Moon syndrome, Boucher-Neuhauser syndrome, Spastic AR 26 58 paraplegia 39

POC1B Cone-rod dystrophy 20 AR 4 7

RPGRIP1L COACH syndrome, Joubert syndrome, Meckel syndrome, Retinal AR 39 49 degeneration in ciliopathy, modifier

SCAPER Retinal dystrophy, Retinitis pigmentosa, , Bardet-Biedl AR 4 7 syndrome

SCLT1 Senior-Loken syndrome, Retinal dystrophy 3

SDCCAG8 Bardet-Biedl syndrome, Senior-Loken syndrome AR 14 18

TCTEX1D2 Short-rib thoracic dysplasia 17 with or without polydactyly, Jeune AR 4 6 Asphyxiating Thoracic Dystrophy

TCTN1 Joubert syndrome AR 6 6

TCTN2 Joubert syndrome, Meckel syndrome AR 20 15

TCTN3 Orofaciodigital syndrome (Mohr-Majewski syndrome), Joubert syndrome AR 9 12

TMEM107 Joubert syndrome AR 10 3

TMEM138 Joubert syndrome AR 6 8

TMEM216 Joubert syndrome, Meckel syndrome AR 17 8

https://blueprintgenetics.com/ TMEM231 Joubert syndrome, Meckel syndrome AR 12 19

TMEM237 Joubert syndrome AR 7 11

TMEM67 Nephronophthisis, COACH syndrome, Joubert syndrome, Meckel AR 87 170 syndrome

TRAF3IP1 Senior-Loken syndrome 9 AR 11 15

TRIM32 Bardet-Biedl syndrome, Muscular dystrophy, limb-girdle AR 13 16

TTC21B Short-rib thoracic dysplasia, Nephronophthisis, Asphyxiating thoracic AR 23 63 dysplasia (ATD; Jeune)

TTC8 Bardet-Biedl syndrome, Retinitis pigmentosa AR 5 16

USP9X Mental retardation, X-linked 99, Mental retardation, X-linked 99, XL 30 27 syndromic, female restricted

WDPCP Meckel-Gruber syndrome, modifier, Bardet-Biedl syndrome, Congenital AR 6 8 heart defects, hamartomas of tongue, and polysyndactyly

WDR19 Retinitis pigmentosa, Nephronophthisis, Short -rib thoracic dysplasia with AR 33 43 or without polydactyly, Senior-Loken syndrome, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Asphyxiating thoracic dysplasia (ATD; Jeune)

WDR34 Short -rib thoracic dysplasia with or without polydactyly, Asphyxiating AR 18 21 thoracic dysplasia (ATD; Jeune)

WDR35 Cranioectodermal dysplasia (Levin-Sensenbrenner) type 1, AR 28 31 Cranioectodermal dysplasia (Levin-Sensenbrenner) type 2, Short rib- polydactyly syndrome type 5

WDR60 Short-rib thoracic dysplasia 8 with or without polydactyly AR 12 13

ZIC3 Heterotaxy, visceral, VACTERL association, Congenital heart defects, XL 15 41 nonsyndromic

ZNF423 Nephronophthisis, Joubert syndrome AD/AR 10 7

*Some regions of the gene are duplicated in the genome. Read more.

# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads), and/or the gene has exons listed under Test limitations section that are not included in the panel as they are not sufficiently covered with high quality sequence reads.

The sensitivity to detect variants may be limited in marked with an asterisk (*) or number sign (#). Due to possible limitations these genes may not be available as single gene tests.

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), mitochondrial (mi), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Mitomap databases.

https://blueprintgenetics.com/ Non-coding disease causing variants covered by the panel

Gene Genomic HGVS RefSeq RS-number location HG19

BBS1 Chr11:66291105 c.951+58C>T NM_024649.4

BBS4 Chr15:73001820 c.77-216delA NM_033028.4 rs113994189

BBS5 Chr2:170354110 c.619-27T>G NM_152384.2

C21ORF2 Chr21:45750232 c.1000-23A>T NM_001271441.1

CEP290 Chr12:88462434 c.6012-12T>A NM_025114.3 rs752197734

CEP290 Chr12:88494960 c.2991+1655A>G NM_025114.3 rs281865192

CEP290 Chr12:88508350 c.1910-11T>G NM_025114.3

CEP290 Chr12:88534822 c.103-18_103-13delGCTTTT NM_025114.3

DYNC2H1 Chr11:103019205 c.2819-14A>G NM_001080463.1 rs781091611

DYNC2H1 Chr11:103055609 c.6478-16G>A NM_001080463.1 rs376892534

DYNC2LI1 Chr2:44027968 c.658-9delT NM_001193464.1 rs752971070

EVC Chr4:5749725 c.940-150T>G NM_153717.2

IFT122 Chr3:129207087 c.2005-13T>A NM_052985.3

IFT140 Chr16:1576595 c.2577+25G>A NM_014714.3 rs1423102192

OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283

OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865

OFD1 ChrX:13773249 c.1130-20_1130-16delTTGGT NM_003611.2

PKD1 Chr16:2140209 c.12445-14T>C NM_001009944.2

PKD1 Chr16:2147825 c.10167+25_10167+43delGGCTGGGCTGGGGGTCCTG NM_001009944.2 rs1197421698

PKD1 Chr16:2152273 c.9202-16G>A NM_001009944.2

PKD2 Chr4:88940551 c.596-59A>G NM_000297.3 rs750504141

PKHD1 Chr6:51618610 c.8798-459C>A NM_138694.3

PKHD1 Chr6:51747238 c.7350+653A>G NM_138694.3

PMM2 Chr16:8891573 NM_000303.2

PMM2 Chr16:8898599 c.179-25A>G NM_000303.2 rs760689221

PMM2 Chr16:8926102 c.640-15479C>T NM_000303.2 rs1258107584

PMM2 Chr16:8941558 c.640-23A>G NM_000303.2

TMEM231 Chr16:75575364 c.824-11T>C NM_001077416.2

https://blueprintgenetics.com/ WDR35 Chr2:20151929 c.1434-684G>T NM_001006657.1

WDR35 Chr2:20182313 c.143-18T>A NM_001006657.1

Test Strengths

The strengths of this test include:

CAP accredited laboratory CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance Careful construction of clinically effective and scientifically justified gene panels Some of the panels include the whole mitochondrial genome (please see the Panel Content section) Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level Our publicly available analytic validation demonstrating complete details of test performance ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see ‘Non-coding disease causing variants covered by this panel’ in the Panel Content section) Our rigorous variant classification scheme Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data Our comprehensive clinical statements

Test Limitations

The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: CC2D2A (NM_020785:7), IFT81 (NM_031473:12), KIAA0586 (NM_001244189:6, 33), RPGRIP1L (NM_015272:23), SCLT1 (NM_001300898:6), TCTN1 (NM_001173976:2;NM_024549:6). Genes with suboptimal coverage in our assay are marked with number sign (#) and genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. Gene is considered to have suboptimal coverage when >90% of the gene's target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not d etect the following:

Complex inversions Gene conversions Balanced translocations Some of the panels include the whole mitochondrial genome (please see the Panel Content section) Repeat expansion disorders unless specifically mentioned Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:

Low level mosaicism in nuclear genes (variant with a minor fraction of 14.6% is detected with 90% probability) Stretches of mononucleotide repeats Low level heteroplasmy in mtDNA (>90% are detected at 5% level) Indels larger than 50bp Single exon deletions or duplications Variants within pseudogene regions/duplicated segments Some disease causing variants present in mtDNA are not detectable from blood, thus post-mitotic tissue such as skeletal muscle may be required for establishing molecular diagnosis.

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

https://blueprintgenetics.com/ For additional information, please refer to the Test performance section and see our Analytic Validation.

Test Performance

The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sectioned from our high-quality, clinical grade NGS assay. Please see our sequencing and detection performance table for details regarding our ability to detect different types of alterations (Table).

Assays have been validated for various sample types including EDTA-blood, isolated DNA (excluding from formalin fixed paraffin embedded tissue), saliva and dry blood spots (filter cards). These sample types were selected in order to maximize the likelihood for high-quality DNA yield. The diagnostic yield varies depending on the assay used, referring healthcare professional, hospital and country. Plus analysis increases the likelihood of finding a genetic diagnosis for your patient, as large deletions and duplications cannot be detected using sequence analysis alone. Blueprint Genetics’ Plus Analysis is a combination of both sequencing and deletion/duplication (copy number variant (CNV)) analysis.

The performance metrics listed below are from an initial validation performed at our main laboratory in Finland. The performance metrics of our laboratory in Seattle, WA, are equivalent.

Performance of Blueprint Genetics high-quality, clinical grade NGS sequencing assay for panels.

Sensitivity % (TP/(TP+FN) Specificity %

Single nucleotide variants 99.89% (99,153/99,266) >99.9999%

Insertions, deletions and indels by sequence analysis

1-10 bps 99.2% (7,745/7,806) >99.9999%

11-50 bps 99.13% (2,524/2,546) >99.9999%

Copy number variants (exon level dels/dups)

1 exon level deletion (heterozygous) 100% (20/20) NA

1 exon level deletion (homozygous) 100% (5/5) NA

1 exon level deletion (het or homo) 100% (25/25) NA

2-7 exon level deletion (het or homo) 100% (44/44) NA

1-9 exon level duplication (het or homo) 75% (6/8) NA

Simulated CNV detection

5 exons level deletion/duplication 98.7% 100.00%

Microdeletion/-duplication sdrs (large CNVs, n=37))

Size range (0.1-47 Mb) 100% (25/25)

The performance presented above reached by Blueprint Genetics high-quality, clinical grade NGS sequencing assay with the following coverage metrics

https://blueprintgenetics.com/ Mean sequencing depth 143X

Nucleotides with >20x sequencing coverage (%) 99.86%

Performance of Blueprint Genetics Mitochondrial Sequencing Assay.

Sensitivity % Specificity %

ANALYTIC VALIDATION (NA samples; n=4)

Single nucleotide variants

Heteroplasmic (45-100%) 100.0% (50/50) 100.0%

Heteroplasmic (35-45%) 100.0% (87/87) 100.0%

Heteroplasmic (25-35%) 100.0% (73/73) 100.0%

Heteroplasmic (15-25%) 100.0% (77/77) 100.0%

Heteroplasmic (10-15%) 100.0% (74/74) 100.0%

Heteroplasmic (5-10%) 100.0% (3/3) 100.0%

Heteroplasmic (<5%) 50.0% (2/4) 100.0%

CLINICAL VALIDATION (n=76 samples)

All types

Single nucleotide variants n=2026 SNVs

Heteroplasmic (45-100%) 100.0% (1940/1940) 100.0%

Heteroplasmic (35-45%) 100.0% (4/4) 100.0%

Heteroplasmic (25-35%) 100.0% (3/3) 100.0%

Heteroplasmic (15-25%) 100.0% (3/3) 100.0%

Heteroplasmic (10-15%) 100.0% (9/9) 100.0%

Heteroplasmic (5-10%) 92.3% (12/13) 99.98%

Heteroplasmic (<5%) 88.9% (48/54) 99.93%

Insertions and deletions by sequence analysis n=40 indels

Heteroplasmic (45-100%) 1-10bp 100.0% (32/32) 100.0%

Heteroplasmic (5-45%) 1-10bp 100.0% (3/3) 100.0%

Heteroplasmic (<5%) 1-10bp 100.0% (5/5) 99,997%

SIMULATION DATA /(mitomap mutations)

Insertions, and deletions 1-24 bps by sequence analysis; n=17

Homoplasmic (100%) 1-24bp 100.0% (17/17) 99.98%

https://blueprintgenetics.com/ Heteroplasmic (50%) 100.0% (17/17) 99.99%

Heteroplasmic (25%) 100.0% (17/17) 100.0%

Heteroplasmic (20%) 100.0% (17/17) 100.0%

Heteroplasmic (15%) 100.0% (17/17) 100.0%

Heteroplasmic (10%) 94.1% (16/17) 100.0%

Heteroplasmic (5%) 94.1% (16/17) 100.0%

Copy number variants (separate artifical mutations; n=1500)

Homoplasmic (100%) 500 bp, 1kb, 5 kb 100.0% 100.0%

Heteroplasmic (50%) 500 bp, 1kb, 5 kb 100.0% 100.0%

Heteroplasmic (30%) 500 bp, 1kb, 5 kb 100.0% 100.0%

Heteroplasmic (20%) 500 bp, 1kb, 5 kb 99.7% 100.0%

Heteroplasmic (10%) 500 bp, 1kb, 5 kb 99.0% 100.0%

The performance presented above reached by following coverage metrics at assay level (n=66)

Mean of medians Median of medians

Mean sequencing depth MQ0 (clinical) 18224X 17366X

Nucleotides with >1000x MQ0 sequencing coverage (%) (clinical) 100%

rho zero line (=no mtDNA), mean sequencing depth 12X

Bioinformatics

The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical Interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements

https://blueprintgenetics.com/ that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the ACMG guideline 2015.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling the following criteria are not Sanger confirmed: the variant quality score is above the internal threshold for a true positive call, and visual check-up of the variant at IGV is in-line with the variant call. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation variant databases used to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.

ICD Codes

Refer to the most current version of ICD-10-CM manual for a complete list of ICD-10 codes.

Sample Requirements

Blood (min. 1ml) in an EDTA tube Extracted DNA, min. 2 μg in TE buffer or equivalent Saliva (Please see Sample Requirements for accepted saliva kits)

Label the sample tube with your patient's name, date of birth and the date of sample collection.

We do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue. In addition, if the patient is affected with a hematological malignancy, DNA extracted from a non-hematological source (e.g. skin fibroblasts) is strongly recommended.

Please note that, in rare cases, mitochondrial genome (mtDNA) variants may not be detectable in blood or saliva in which case DNA extracted from post-mitotic tissue such as skeletal muscle may be a better option.

Read more about our sample requirements here.

https://blueprintgenetics.com/ For Patients

Other

Bardet Biedl Syndrome Family Association Bardet-Biedl Australia Ciliopathy Alliance Clinical Registry Investigating Bardet-Biedl Syndrome Clinical Registry Investigating Bardet-Biedl Syndrome GeneReviews - Bardet-Biedl Syndrome GeneReviews - Joubert Syndrome GeneReviews - Nephronophthisis GeneReviews - Primary Ciliary Dyskinesia Hartill V et al. Meckel-Gruber Syndrome: An Update on Diagnosis, Clinical Management, and Research Advances. Front Pediatr. 2017 Nov 20;5:244. Joubert Syndrome UK Joubert Syndrome and Related Disorders Foundation NORD - Bardet-Biedl Syndrome NORD - Joubert Syndrome NORD - Meckel Syndrome NORD - Primary Ciliary Dyskinesia PCD Family Support Group PCD Foundation Reiter JF et al. Genes and molecular pathways underpinningciliopathies. Nat Rev Mol Cell Biol.2017 Sep;18(9):533-547

https://blueprintgenetics.com/